Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Acknowledgement is hereby made of receipt and entry of the communication filed on Nov. 17, 2025. Claims 1-20 are pending. Claims 1, 3-4, 6 and 8 are currently examined. Claims 2, 5, 7 and 9-20 are withdrawn.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(Previous rejection- maintained) Claims 1, 3-4, 6 and 8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Naso et al. (BioDrugs. 2017 Aug;31(4):317-334).
Claims 1, 3-4, 6 and 8 are directed to a pharmaceutical composition comprising the recombinant adeno-associated virus (rAAV), wherein the rAAV is produced by a method comprising: obtaining a desired template DNA sequence containing a [ITR-cargo-ITR] DNA sequence motif; designing a PCR primer pair such that the 3' terminus of both the forward and reverse PCR primers overlap only about the last 2-8 bases of the A/A' ITR sequences and the 5' terminus of both the forward and reverse PCR primers extend into about 20-35 bases of the flanking sequences; performing a PCR amplification reaction with PCR cycling parameters comprising a combined annealing/extension step at a temperature greater than 70°C, wherein the PCR amplification reaction contains one or more osmolytes, thereby producing a plurality of amplicon polynucleotides containing the desired [ITR-cargo-ITR] DNA sequence motif, obtaining a quantity of the AAV rep/cap DNA sequence; obtaining a quantity of AAV helper DNA sequence; transfecting the amplicon polynucleotides containing the desired [ITR-cargo-ITR] DNA sequence motif, the AAV rep/cap DNA sequence and the AAV helper DNA sequence into a packaging cell line; expanding the packaging cell line; lysing cells of the packaging cell line; and purifying the lysed cells to collect a quantity of rAAV.
These claims are product-by-process claims, which are drawn to a pharmaceutical composition comprising the recombinant adeno-associated virus (rAAV). The method steps recited to produce the rAAV are not considered when determining patentability of the product (MPEP § 2113). In In re Thorpe, the court stated, “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). (Emphasis added)
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Naso et al. teaches a rAAV vector for expressing the gene of interest in a cassette as [ITR-cargo-ITR] DNA sequence motif as claimed (See Fig. 1 of Naso et al. below) and it can be delivered into a subject for gene therapy application such as intramuscular delivery and pulmonary delivery (See e.g. page 328, right column, paragraph 4; page 327, right column), which indicates that the rAAV is used as the pharmaceutical composition.
Naso et al. teaches that the method used for producing rAAV involves transfecting HEK293 cells with either two or three plasmids: one encoding the gene of interest ([ITR-GeneofInterest-ITR]), one carrying the AAV rep/cap genes, and another containing helper genes provided by either adeno or herpes viruses (See page 322, left column, paragraph 2). Fig. 2 of Naso et al. further teaches the process of AAV production and purification (See page 322, Fig. 2).
Accordingly, the recombinant AAV of Naso et al. anticipates the claimed recombinant AAV, even though the AAV of Naso et al. was made by a slightly different process.
Responses to Applicant’s Remarks
Applicant’s arguments filed on Nov. 17, 2025 has been received and fully considered.
Applicant’s arguments on the rejections under 35 U.S.C. §102 is not found persuasive as follows:
1). Applicant argued that Naso does not teach or suggest rAAV produced from amplicon DNA templates (See Remarks, page 9).
The argument is not persuasive.
a). Applicant allegedly listed a serial of elements such as amplicon, temperature, primers, osmolytes and primers overlapping only the terminal 2-8 bases of the A/A' ITR and 20-35 bases of flanking sequence in order to show the difference between Naso’s teaching and the instant claims. However, these listed conditions are all related to the process steps that generated the same product as claimed in claim 1, [ITR-cargo-ITR].
Per the MPEP 2113, product-by-process claims are limited to the final end-product claimed, and that the process steps are not considered unless the process steps impart distinctive structural characteristics to the final product. That is, the patentability of the product does not depend on the process claimed. This means so long as the claimed product is the same as (e.g., anticipated) or only an obvious variant of a prior art product, then the claimed product is not patentable. The MPEP view is also supported by case law. See, e.g., In re Thorpe, 777 F.2d 695, 697-98 (Fed. Cir. 1985) (“For this reason, even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself.”).
b). As a review article, Naso teaches [ITR-cargo-ITR] as reflected in Fig. 1 (See Naso, page 319) that is comparable to the claimed product [ITR-cargo-ITR], AAV helper and/or rep/cap constructs.
c). The instant specification discloses that the PCR produced [ITR-cargo-ITR] construct may be transfected into packaging cell lines (such as HEK293 or other cell lines known in the art) along with conventional AAV helper and rep/cap plasmids to produce rAAV. The PCR produced [ITR-cargo-ITR] construct may also be transfected into packaging cell lines along with AAV helper and rep/cap constructs, wherein one or both constructs are amplicon polynucleotides manufactured by PCR. The packaging cell lines may be optimized for use with PCR produced [ITR-cargo-ITR] constructs and/or AAV helper and rep/cap constructs wherein one or both are manufactured by PCR. PCR-produced [ITR-cargo-ITR], AAV helper and rep/cap constructs may be produced by large-scale PCR. The largescale PCR may be continuous flow (See instant specification, [ 0050]), which is taught by Naso.
2). Applicant argued that structural identity between the claimed rAAV and Naso's rAAV is not established by arguing that the amplicon-derived genomes lack plasmid backbone remnants, Amplicon methods produce cleaner, shorter, backbone-free genomes, resulting in known differences for packaged genome length, ratio, level of encapsidated impurities, and methylation/CpG composition.
These arguments are not persuasive because these conditions are not limitations in the instant claims. Further, applicant has not provided any evidence/data to support these arguments or to demonstrate that the [ITR-cargo-ITR] construct of Naso is structurally different from the claimed [ITR-cargo-ITR] construct.
In addition, the applicant argued that Naso discloses only rAAV produced via plasmid transfection, a process known in the art to yield different genomic impurity profiles, different heterogeneous packaging populations, and different structural characteristics. Again, applicant has not provided any evidence/data to support these arguments or to demonstrate that the [ITR-cargo-ITR] construct of Naso possesses these features.
3). Applicant argued that Product-by-Process limitations are distinguishing when they produce a structurallv/functionallv different product (See Remarks, page 10).
Applicant’s argument is not persuasive.
First, the end product claimed in the instant application is a rAAV that was produced by transfecting, inter alia, “the amplicon polynucleotides containing the desired [ITR-cargo-ITR] DNA sequence motif”. There is no specific structure or sequence defining the claimed [ITR-cargo-ITR] construct. The structure of Naso is also a polynucleotide containing [ITR-cargo-ITR].
Second, Naso teaches the same structure of [ITR-cargo-ITR] in the review (See page 319, Table 1 and below). The schematic representation is applicable to be used to show the structure of Naso, which is also described in Naso’s page 318, right column, paragraph 3, and the product teaches the claimed products [ITR-cargo-ITR].
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Third, as the argument about “distinct encapsidated impurity profile”, it is also not persuasive because there is no limitation for the impurity in the instant claims.
4). Applicant argued that Naso's high-level discussion of ITR-Flanked cassettes does not render the claimed rAAV Identical (See Remarks, page 10).
Applicant’s argument is not persuasive.
First, the end product claimed in the instant base claim 1 is [ITR-cargo-ITR]. There is no specific structure or sequence defining the claimed [ITR-cargo-ITR] construct. The structure of Naso is also a polynucleotide containing [ITR-cargo-ITR].
Second, the instant specification discloses that “the term "ITR" means inverted terminal repeat DNA sequence. The ITR sequence may be wild-type and comprise 145 bases each. The ITR sequence may also be modified and may be comprised of more or less than 145 bases. The ITR may be comprised of wild-type A, B, C and D elements, or one or more of said elements may be modified (See instant specification, [0037]). Therefore, Naso teaches the ”ITR” claimed in the instant specification by stating that “these coding sequences are flanked by inverted terminal repeats (ITRs) that are required for genome replication and packaging” (See Naso, page 318, left column, paragraph 2).
In addition, the alleged argument on “osmolyte-assisted high-temperature ITR amplification” is also not persuasive because the process steps are not patentable in this “product-by-process claims” (See MPEP 2113).
5). Applicant also argued on page 8 that “this PCR-based generation of the transgene cassette with specific primer architecture and stringent high-temperature amplification in the presence of osmolytes is not taught or suggested by Naso. Instead, Naso teaches standard plasmid-based transfection protocols, where the transgene cassette is cloned into plasmid vectors…” (See Remarks, page 8).
Applicant’s argument is not persuasive.
Based on the description above in items 1) to 4), Naso teaches the same product of [ITR-cargo-ITR] as claimed. As for the stringent high-temperature amplification in the presence of osmolytes, the determination of patentability is based on the product itself and the patentability of a product does not depend on its method of production (MPEP § 2113)
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUIXUE WANG whose telephone number is (571)272-7960. The examiner can normally be reached Monday-Friday 8:00 am-5:00 pm, EST.
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/RUIXUE WANG/ Examiner, Art Unit 1672
/NICOLE KINSEY WHITE/ Primary Examiner, Art Unit 1672